Purpose. This study was designed to determine (1) rates of clinically meaningful tumor reduction in breast tumor size following neoadjuvant chemotherapy (NAC), (2) which receptor subtypes and MRI phenotypes are associ- ated with clinically meaningful tumor reduction, and (3) whether MRI phenotype impacts concordance between pathologic and MRI size. Methods. We analyzed data from the I-SPY TRIAL, a multicenter, prospective NAC trial. Reduction in tumor size from [4 to B4 cm was considered clinically mean- ingful, as crossing this threshold was considered a reasonable cutoff for potential breast conservation therapy (BCT). MRI phenotypes were scored between one (well- defined) and five (diffuse) on pre-NAC MRIs. Results. Of 174 patients with tumors [4 cm, 141 (81 %) had clinically meaningful tumor reduction. Response to therapy varied by MRI phenotype (p = 0.003), with well- defined phenotypes more likely than diffuse phenotypes to have clinically meaningful tumor shrinkage (91 vs. 72 %, p = 0.037). Her2? and triple-negative (Tneg) tumors had the highest rate of clinically meaningful tumor reduction (p = 0.005). The concordance between tumor diameter on MRI and surgical pathology was highest for Her2? and Tneg tumors, especially among tumors with solid imaging phenotypes (p = 0.004). Discussion. NAC allows most patients with large breast tumors to have clinically meaningful tumor reduction, meaning response that would impact ability to undergo BCT. However, response varies by imaging and tumor subtypes. Concordance between tumor size on MRI and surgical pathology was higher in well-defined tumors, especially those with a Tneg subtype, and lower in HR+ diffuse tumors.